Objective: Transduction of peripheral inflammatory signals across the blood brain barrier (BBB) occurs by both humoral [e.g., via the organum vasculosum laminae terminalis (OVLT)] and neural (e.g., via the hepatic vagus nerve) routes. The involvement of blood amphipathic mediators [prostaglandin E2 (PGE2), arachidonic acid (AA), platelet activating factor (PAF), and nitric oxide (NO)] in this transduction is neglected, because, in the free form, these mediators are rapidly deactivated in the circulation. However, endogenous amphipaths exist in the blood mostly in the bound form. They are bound to transport proteins, such as serum albumin. Serum albumin protects amphipathic mediators from degradation and delivers them to their targets. Hypothesis. Albumin transduces peripheral inflammatory signals across the BBB by delivering blood born PGE2, AA, PAF, and NO to the perivascular space of the OVLT and/or to vagal terminals. To test this hypothesis, we will take a multidisciplinary approach, involving physiological, biochemical, neurosurgical, and histological techniques. The fever response will be used as a physiological marker of systemic inflammation. Specific Aims: 1. Determine whether serum albumin is essential for the development of fever. We will study the febrile response in inherently analbuminemic vs. normalbuminemic rats. 2. Ascertain whether binding with serum albumin increases the pyrogenic activity of amphipathic fever mediators administered peripherally. We will compare the febrile responses of normalbuminemic rats to the albumin bound vs. free form of PGE2, AA, PAF and NO. 3. Establish major targets for the albumin bound mediators of fever. We will study the febrile responsiveness to albumin complexes of PGE2, PAF, and NO in normalbuminemic rats with electrolytic OVLT ablation or selective hepatic vagotomy. Significance. A novel mechanism of the transduction of peripheral inflammatory signals across the BBB is suggested: transport of blood born amphipathic mediators (PGE2, AA, PAF, and NO) by serum albumin. This mechanism, if confirmed, will constitute a new target for therapeutic interventions in systemic inflammation.